Activation of CpG-Rich Promoters Mediated by MLL Drives MOZ-Rearranged Leukemia
Activation of CpG-Rich Promoters Mediated by MLL Drives MOZ-Rearranged Leukemia
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DOI：
10.1016/j.celrep.2020.108200
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发表时间：
2020-09-29
期刊：
影响因子：
8.8
通讯作者：
Yokoyama, Akihiko
中科院分区：
文献类型：
--
作者：
Miyamoto, Ryo;Okuda, Hiroshi;Yokoyama, Akihiko
不受控制的造血祖细胞自我更新诱导白血病。为了自我更新，白血病细胞必须不断激活之前在母细胞中活跃的基因。在这里，我们描述了一个负责致癌自我更新的交易激活系统的电路。MLL通过其CXXC结构域将RNA聚合酶II （RNAP2）招募到未甲基化的富含cpg的启动子上，并通过转录调节因子激活转录，包括AF4家族/ENL家族/P-TEFb复合物、DOT1L和p300/CBP组蛋白乙酰转移酶。MOZ还通过与RNAP2和MLL的关联靶向广泛的富含cpg的启动子。白血病融合蛋白如MOZ-TIF2和MLL-AFX通过异常募集p300/CBP来组成性地激活富含cpg的启动子。药理抑制MLL或DOT1L可诱导moz - tif2转化的细胞分化。这些结果表明，MLL介导的非甲基化的富含cpg的启动子激活是MLL重排白血病癌性自我更新的核心机制，并表明针对MLL重排白血病的分子靶向治疗可以应用于MLL重排白血病。
Uncontrolled self-renewal of hematopoietic progenitors induces leukemia. To self-renew, leukemia cells must continuously activate genes that were previously active in their mother cells. Here, we describe the circuitry of a transactivation system responsible for oncogenic self-renewal. MLL recruits RNA polymerase II (RNAP2) to unmethylated CpG-rich promoters by its CXXC domain and activates transcription by transcriptional regulators, including the AF4 family/ENL family/P-TEFb complex, DOT1L, and p300/CBP histone acetyl transferases. MOZ also targets a broad range of CpG-rich promoters through association with RNAP2 and MLL. Leukemic fusion proteins such as MOZ-TIF2 and MLL-AFX constitutively activate CpG-rich promoters by aberrantly recruiting p300/CBP. Pharmacological inhibition of MLL or DOT1L induces differentiation of MOZ-TIF2-transformed cells. These results reveal that activation of unmethylated CpG-rich promoters mediated by MLL is the central mechanism of oncogenic self-renewal in MOZ-rearranged leukemia and indicate that the molecularly targeted therapies intended for MLL-rearranged leukemia can be applied for MOZ-rearranged leukemia.